YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer's Disease

Background Disease modifying therapies for Alzheimer's disease (AD) would be most effective during the preclinical stage (pathology present, cognition intact) before significant neuronal loss occurs Therefore biomarkers that detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design Methods AD-associated changes in cerebrospinal fluid (CSF) were measured using two dimensional difference gel electrophoresis and liquid chromatography tandem mass spectrometry Subsequently CSF YKL 40 was measured by enzyme linked immunosorbent assay in the discovery cohort (n = 47) validation cohort (n = 292) with paired plasma samples (n = 237), frontotemporal lobar degeneration (PSP n = 9) and progressive supranuclear palsy (PSP n = 6) Immunohistochemistry was performed to identify source(s) of YKL 40 in human AD brain Results Discovery and validation cohorts showed higher mean CSF YKL 40 in very mild and mild AD type dementia (Clinical Dementia Rating [CDR] 0 5 and 1) versus control subjects (CDR 0) and PSP subjects Importantly, CSF YKL 40/A beta 42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR > 0 conversion) as well as the best CSF biomarkers identified to date tau/A beta 342 and p tau 181/A beta 42 Mean plasma YKL-40 was higher in CDR 05 and 1 versus CDR 0 and correlated with CSF levels YKL 40 immunoreactivity labeled astrocytes near a subset of amyloid plaques implicating YKL-40 in the neuroinflammatory response to A beta deposition Conclusions These data demonstrate that YKL 40, a putative indicator of neuroinflammation is elevated in AD and together with A beta 42 has potential prognostic utility as a biomarker for preclinical AD